The limited number of existing studies investigating the simultaneous effects of crumb rubber modifier (CRM), waste engine oil (WEO), and polyphosphoric acid (PPA) has resulted in a significant knowledge gap in the design of high-performance, cost-effective, and environmentally sustainable asphalt binders and pavements. Accordingly, this study aims to evaluate the combined influence of these modifiers on the rheological and performance-related properties of a semi-synthetic asphalt binder. Key performance indicators, including viscosity, rutting resistance, fatigue behavior, and temperature-dependent performance, were systematically investigated. The results indicate that binder viscosity is strongly influenced by the WEO content; increasing WEO significantly reduces viscosity, thereby improving mixing, pumping, and workability characteristics. In contrast, higher CRM contents lead to increased viscosity and enhanced resistance to high-temperature deformation under heavy traffic loading conditions. Findings from the MSCR and LAS tests demonstrate that an optimal balance between CRM and WEO can simultaneously improve rutting resistance and fatigue life of the modified binder in a statistically significant manner. Analysis of variance (ANOVA) further reveals that although WEO exhibits a stronger individual effect on binder properties than CRM, the interaction between these two modifiers plays a critical role in regulating the overall performance behavior of the asphalt binder. Based on the comprehensive analysis, three optimal design scenarios were identified: (i) CRM = 25% and WEO = 15% to maintain viscosity within standard allowable limits; (ii) CRM = 25% and WEO = 17.5% to enhance workability through reduced viscosity; and (iii) CRM = 18.6% and WEO = 15% to improve high-temperature performance and resistance under heavy traffic conditions. Overall, the findings of this study provide a scientifically sound, practical, and sustainable approach for enhancing the durability, performance, and environmental compatibility of asphalt pavements, making it suitable for applications under diverse climatic conditions and high traffic demands.